Abstract

Resistance to BRAF and MEK inhibitor (BRAFi+MEKi) in BRAF mutant tumors occurs through heterogeneous mechanisms, including ERK reactivation and autophagy. Little is known about the mechanisms by which ERK reactivation, or autophagy are induced by BRAFi+MEKi. Here we report that in BRAF mutant melanoma cells, BRAFi+MEKi induced SEC61-dependent ER translocation of the MAPK pathway via GRP78 and KSR2. Inhibition of ER translocation prevented ERK reactivation and autophagy. Following ER translocation, ERK exited the ER and was rephosphorylated by PERK. Reactivated ERK phosphorylated ATF4, which activated cytoprotective autophagy. Upregulation of GRP78 and phosphorylation of ATF4 was detected in tumors of patients resistant to BRAFi+MEKi. ER translocation of the MAPK pathway was demonstrated in therapy-resistant patient-derived xenografts. Expression of a dominant negative ATF4 mutant conferred sensitivity to BRAFi+MEKi in vivo. This mechanism reconciles two major targeted therapy resistance pathways and identifies druggable targets, whose inhibition would likely enhance the response to BRAFi+MEKi.